As the study of nociception and pain mechanisms progresses, we are gaining a better understanding of processes that promote, or sensitize the nervous system in a way that actually amplifies the experience of pain for the injured individual. Peripheral sensitization processes increase transduction and transmission of stimuli coded as painful, as well as promote spontaneous signaling miscoded as aberrant stimuli. Such dramatic peripheral activity subsequently leads to sensitization of central pathways which further amplify signaling and further exaggerates the pain experience. Over time, the site of pathology shifts from the direct processes of injury, to the sensitized nervous system to produce a neuropathic pain syndrome.1

Improved understanding of sensitization mechanisms has promoted a growing interest in addressing the peripheral processes directly as a way to reduce nociceptive signaling into the central nervous system (CNS).2,3 Impeding such input would thereby limit central sensitization processes as well.3-5 The most efficient treatment paradigms for any disease process focus treatment to the site of pathology.5,6 Targeted drug delivery methods reduce potential for side-effects, while maximizing drug exposure to the system to be treated.5-7 Due to these considerations, there is a growing interest in ‘targeted peripheral analgesics’ for further investigation and clinical use. Unfortunately, due to the use of medications for “off-label” purposes, and the lack of financial interest for sponsoring studies of “off-patent” drugs, the development of such specific analgesics remain impeded.

Compounding pharmacists have long been associated with reformulating—and often combining—various drugs with alternate delivery forms to reduce side-effects and improve compliance.6-8 At times, compounding a drug may exploit specific drug mechanisms to focus on an explicit pathologic process. Reformulating established drugs, altering the mode of delivery, and combining with other drugs for “off-label” uses is gaining acceptance and utilization, as evidenced by the growth of peer-reviewed literature.5-11

The purpose of this article is to focus on some of the currently used topical applications for pain management, as well as a few potentially evolving approaches.

Topical and Transdermal Delivery

The standard treatment of multiple chronic pain syndromes includes the use of multiple medications that may have limited affect yet multiple side effects. In order to provide care for these patients, doctors are often forced to “think outside of the box,” and rely on medications in an “off label” approach. As a result of such exploration, new uses and delivery methods have been developed for multiple medications. One such new approach is through the utilization of topical and transdermal medications that may potentially have greater effectiveness, with fewer side effects.5-9

The skin can be a very effective portal for drug delivery both locally, as well as systemically. The molecular characteristics of the drug and the solvent can favor either local (topical) or more systemic (transdermal) distribution. Topical formulations typically focus the medication to the localized region of the skin where it is applied. Advantages of this approach include drug delivery in a focused manner and potentially hundreds to thousand times greater concentrations than through oral or parenteral routes. Additionally, systemic side effects would be limited as well.5-7,11

Transdermal drug delivery, like parenteral routes, allows systemic distribution of multiple medications in a way that may potentially reduce GI side effects, as well as potentially allow higher systemic concentrations by bypassing liver first-pass metabolism. Other systemic side-effects, including CNS and cardiovascular responses, would remain of similar concern to oral routes.5,6,9

For the purposes of pain management, topical drug delivery can focus on the specific peripheral mechanisms, including transduction and transmission of nociceptive signaling, to hopefully limit both peripheral and central sensitization processes.1,5,10,12-14

Peripheral Nerve/Tissue Injury

Much of the initial stages of nerve sensitization involve direct peripheral nerve or adjacent tissue injury. Following a local injury, multiple local changes occur that sensitize the local sensory nerve fibers. Multiple substances are released into the milieu, such as acids, substance P, histamine to form a “sensitizing soup” that enhances neural discharges back to the central nervous system, but also enhances firing in adjacent neurons. Antegrade release of neurotransmitters adds further sensitizing substances to the mix. See Figure 1 for an illustration of these processes leading to peripheral sensitization. The net end result is decreasing activation thresholds in nociceptors, spontaneous discharges of nociceptors and axons, and multiple other processes termed peripheral sensitization. Subsequently this sensitization leads to increased quantity of up-regulated sodium and calcium channels in the regional sensory nerves, coupled with enhanced nociceptors sensitivity , increased frequency of spontaneous discharges within the regional neurons, and multiple other progressive processes (beyond the scope of this article) that increase pain signaling centrally.1 Topically applied local anesthetic drugs are the most commonly used agents to address this problem.5-7,9 The targeted administration of these agents may address the local chemical changes and more effectively inhibit the sensitizing processes. Topical agents that focus on the local milieu and processes may also produce fewer side-effects along with greatly enhanced efficacy.

Figure 1.Illustration of the transdermal application of topical agents to focus on the local milieu and peripheral sensitization processes.

Multiple over-the-counter (OTC) agents containing various local anesthetics have been widely used for years ( Solarcaine®). Clinically, topical Lidocaine, Bupivaciane and Tetraciane preparations are used in multiple forms, including lotions, creams, gels, sprays, and more recently patches.15,16 Direct application to wounds prior to bandage changes and debridements greatly improves patient comfort. A 5% lidocaine patch (Lidoderm®) has been shown to be effective for several pain syndromes including local/regional pain complaints, such as post-herpetic neuralgia; as well as more generalized pain complaints, such as low back pain.9,15,16 Additionally, certain antidepressants, such as amitriptyline and doxepin, can also block the sodium and calcium channels and act very similar to local anesthetics.6-8,10,14,17

In addition to the local anesthetic effects, there is good evidence that amitriptyline and similar antidepressants may block pain thru several different mechanisms. Norepinephrine and 5-HT reuptake inhibition; blocking of NMDA, nicotinic, histamine and 5-HT receptors; and activation of adenosine-1 receptors thru enhanced adenosine release are all potentially analgesic actions purported to this class of antidepressant.6,14,17

10.Lynch ME, Clark AJ, and Sawynok J. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clinical Journal of Pain. 2003. 19(5):323-8.

13. Sawynok J and Reid A. Modulation of formalin-induced behaviors and edema by local and systemic administration of dextromethorphan, memantine and ketamine. European Journal of Pharmacology. 2002. 450(2):153-62.

24. Gorman AL, Elliott KJ, and Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neuroscience Letters. 1997. 223(1):5-8.

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